MicroRNAs (miRNAs) have quickly emerged as important regulators of mammalian physiology owing to their precise regulation of critical protein coding genes. Importantly, perturbations in expression or function of specific miRNAs has been linked to a plethora of human pathological conditions including cancer, autoimmunity, cardiovascular disease and neurodegeneration. Although miRNA gene deletion in mice via homologous recombination has led to an improved understanding of how they function during times of health and disease, there remains a fundamental need to manipulate miRNA genes and their target binding sites in the human germ line. This would allow for the study of their biology in man, and may be a strategic means by which miRNAs can be targeted therapeutically to combat human disease. We propose to develop a novel approach to activating, repressing or disrupting human miRNA genes in vivo by engineering TALE proteins that will function as transcription factors or nucleases that specifically target miRNA genes or their binding sites in the 3'UTRs of key target mRNAs. We will focus on targeting human miRNA---155, an oncomiR involved in regulating immune responses, and miR---146a, a tumor suppressor miRNA that inhibits inflammatory responses. Following proper targeting and disruption of these miRNAs or their binding sites in the 3' UTRs of relevant target mRNAs, a series of functional assays will be carried out to assess the roles of human miR---155 and miR---146a in regulating immune responses and cancer phenotypes. Beyond these two miRNAs, this approach will be compatible with any human miRNA making it a powerful, specific and versatile technology that has not yet been used to study miRNAs.